The FDA has taken a significant step towards facilitating the development of psychedelic therapies by issuing draft guidance for sponsors of clinical trials involving psychedelic drugs. This guidance aims to address the unique challenges and considerations associated with studying these substances for the treatment of psychiatric disorders, substance use disorders, and other medical conditions.
The FDA's guidance, titled "Psychedelic Drugs: Considerations for Clinical Investigations Guidance for Industry", focuses on psilocybin, lysergic acid diethylamide (LSD), and methylenedioxymethamphetamine (MDMA). It provides recommendations across several key areas, including chemistry, manufacturing, and controls (CMC); non-clinical studies; clinical pharmacology; abuse potential assessment; and clinical trial design.
Trial Conduct and Psychotherapy
A key recommendation within the guidance is the integration of psychological support, particularly psychotherapy, into psychedelic therapy clinical trials. The FDA acknowledges that the precise contribution of psychotherapy to the observed efficacy of psychedelic treatment remains unclear. To address this, the guidance suggests that sponsors meticulously plan and articulate their rationale for including a psychotherapy component in their trial. Sponsors should also explain any trial design elements intended to mitigate potential bias or quantify the specific contribution of psychotherapy to the overall treatment effect.
To further isolate the effects of the psychedelic drug from the psychotherapy, the FDA suggests a study design that separates patients into two groups: one receiving therapy alone and the other receiving the psychedelic drug in conjunction with therapy. This allows for a more comprehensive understanding of each component’s impact. The guidance also recommends that the therapist overseeing a treatment session should not partake in post-session psychotherapy to prevent potential bias in successive therapy sessions.
Data Collection and Placebo Controls
The FDA acknowledges the challenges associated with using traditional placebos in psychedelic research due to the "intense perceptual disturbances" experienced by participants receiving the active drug. To mitigate this, the guidance suggests the use of psychedelic microdoses or other psychoactive drugs to mimic the drug’s effects in the control group.
The guidance also recommends the deployment of blinding questionnaires for both subjects and investigators/raters to assess the impact of functional unblinding and minimize potential bias. Furthermore, it emphasizes the importance of managing trial-related adverse events and significant hazards, while also considering the feasibility of implementing analogous strategies in the post-marketing phase.
Subject Safety and Abuse Potential
Given that many psychedelic drugs are classified as Schedule I controlled substances, the FDA guidance emphasizes the importance of assessing their abuse potential. Sponsors are encouraged to engage in early discussions with the FDA regarding their plans for these assessments and to consult the agency's 2017 guidance on "Assessment of Abuse Potential of Drugs."
The guidance also addresses the vulnerability of patients during and after psychedelic therapy, recommending the presence of two monitors during treatment sessions: a lead monitor with clinical psychotherapy experience and an assistant monitor with at least one year of clinical experience within a licensed mental healthcare setting. The guidance further stipulates the need for comprehensive disclosure, ensuring that patients are fully aware of the potential for changes in perception, cognition, and judgment that may persist for many hours.
By addressing key considerations related to trial design, data collection, and patient safety, this guidance is expected to foster further research and development in this promising area of mental health treatment. The FDA's support will be instrumental in fostering the field's expansion, driving further research, and ultimately delivering on the promise of creating a new world of mental healthcare that more effectively meets the complex needs of patients.
